Weight reduction is accomplished when the body takes in fewer calories than it expends. Thus, all weight control measures involve strategies for either reducing caloric intake, or, increasing energy expenditure. For example, diets achieve weight reduction by directing an individual to consume food sufficient to maintain nutritional balance but insufficient to maintain body weight. U.S. Pat. No. 4,137,327 to Marshall claims an analogous process whereby a mixture of albumin and oxethazine is swallowed prior to eating. The mixture purportedly clings to the walls of the stomach and anesthetizes the nerve endings which activate digestive fluids. The process thereby permits eating without caloric intake. On the other hand, exercise or activity programs achieve weight reduction by increasing the body's rate of caloric expenditure. Such programs are effective when they specify normal levels of food consumption and greater than normal levels of exercise.
It follows that the most efficient weight reduction strategy would simultaneously decrease caloric intake while increasing caloric expenditure. To this end, dehydroepiandrosterone ("DHEA") is a promising antiobesity agent. The exact mechanism by which DHEA effects weight loss is not known. However, experimental evidence suggests that DHEA inhibits particular metabolic enzymes (and thus caloric intake) while simultaneously increasing the overall metabolic rate (and therefor caloric expenditure).
For instance, as to its inhibitory effect, DHEA is known to inhibit mammalian glucose-6-phosphate dehydrogenase ("G6PD"). Marks, P. A. and J. Banks. 1960. Inhibition of glucose-6-phosphate dehydrogenase by steroids. PNAS USA 16:447-452; Oertel, G. W. and P. Benes. 1972. The effect of steroids on glucose-6-phosphate dehydrogenase. J. Steroid Biochem. 3:493-496; Lane, M. D. and J. Moss. 1971, in Vogel, H. J. (ed) Metabolic Pathways. Vol. 5. Academic Press. New York. Pg. 23. G6PD is the first enzyme in the pentosephosphate shunt, a primary source of extra-mitochondrial NADPH required for the biosynthesis of fatty acids and nucleic acids. The results of DHEA treatment in mice, where decreases in lipogenesis and fat cell size were found, suggest a primary effect on lipogenesis in vivo. Yen, T. T., J. A. Allan, D. V. Pearson, J. M. Acton and M. M. Greenberg. 1977. Prevention of obesity in A.sup.vy /a mice by dehydroepiandrosterone. Lipids 12:409-413; Cleary, M. P., R. Seidenstat, R. H. Tannen, and A. G. Schwartz, 1982. The effect of dehydroepiandrosterone on adipose tissue cellularity in mice. Proc. Soc. Exp. Biol. Med. 171:276.
DHEA is also a known inhibitor of NADH oxidase, the first enzyme of the cytochrome system. Crane, F. L., Y. Hatefi, R. L. Lester, and C. Widmer. 1957. Isolation of a quinone from beef heart mitochondria. Biochim. Biophys. Acta. 25:220-221. Cytochrome is an indispensable component of mitochondrial oxidative phosphorylation, the principal source of ATP required for the biosynthesis of fatty acids. Thus, by limiting the availability of mitochondrial ATP, DHEA may inhibit the process of fat deposition.
In addition, DHEA is known to directly inhibit fatty acid synthetase. Spydevold, B. O., A. L. Greenbaum, N. Z. Baguer, and P. McLean, 1978, Adaptive responses of enzymes of carbohydrate and lipid metabolism to dietary alteration in geneticallv obese Zucker rats (fa/fa), Eur. J. Biochem., 89:329-339; Michaelis, O. E., D. J. Scholfield, L. B. Gardner, and S. Cataland. 1980. Metabolic responses of Zucker fatty and lean rats fed carbohydrate diets ad libitum or in meals, J. Nutr. 110:1409-1420. Prolonged treatment with DHEA is known to decrease liver and adipose tissue fatty acid synthetase activity in mice characterized by excessive levels of this enzyme. Shepherd, A. and M. P. Cleary, 1984. Metabolic alterations after dehydroepiandrosterone treatment in Zucker rats. Am. J. Physiol. 246:E123-E128.
Finally, DHEA is known to inhibit 11.beta.-hydroxylase, an enzyme complex that converts 11-deoxycorticosterone to aldosterone and 11-deoxycortisol to cortisol. Sharma, D. C., E. Forchielli, and R. I. Dorfman. 1963. Inhibition of enzymatic 11.beta.-hydroxylation bv androgens. J. Biol. Chem. 238:572-575. Since hypercorticism is a prominent feature of genetically obese mice, occurring after the onset of obesity, DHEA could limit the production of glucocorticoids and restore a more normal hormonal balance, thereby decreasing the severity of obesity.
In connection with its metabolic rate effects, DHEA is known to increase levels of thyroid stimulating hormone and thyroxine in the blood. Tal, B. and F. G. Sulman. 1973. Dehydroepiandrosterone-induced thyrotropin release in immature rats. J. Endocrinol. 57:183-184; Tal, B. and F. G. Sulman. 1975. Dehydroepiandrosterone-induced thyrotropn release during heat stress in rats. J. Endrocrinol. 67:99-103. In rat studies, such increases are accompanied by hypertrophy of the thyroid follicle epithelium, suggesting that the anti-obesity effect of DHEA may also be the result of an increase in metabolic rate. Id.; Tagliaferro, A. R. and J. R. Davis. 1983. The effective of dehyroepiandrosterone on caloric intake, body weight and resting metabolism. Fed. Proc. 42:326.
It is hypothesized that the anti-obesity effects of DHEA are accomplished by its metabolic by-products, principally .alpha.-hydroxy-etiocholanone (5-.beta.-androstan-3-.beta.-ol-17-one, hereinafter ".alpha.-HET"), and, .beta.-hydroxy-etiocholanone (5-.beta.-androstan-3-.beta.-ol-17-one, hereinafter ".beta.-HET"). Coleman, Leiter and Applezweig, Therapeutic Effects of Dehydroepiandrosterone Metabolites in Diabetes Mutant Mice, Endocrinology, 115(1), 239. The conversion of DHEA to .alpha.-HET and .beta.-HET sometimes occurs intracellularly, where these products then exert effects on the biochemical machinery of individual cells.
The compounds and methods disclosed in the prior art serve as background for the design of anti-obesity DHEA compounds. For one, although DHEA itself exhibits relatively low toxicity in humans, the anti-obesity effects cannot be accomplished by administration of large doses. Indeed, DHEA can also be metabolized to estrogens, a process known to stimulate uterine growth in the sexually immature rat. Knudsen, T. T. and V. B. Mahesh, 1975, Initiation of precocious sexual maturation in the immature rat treated with dehydroepiandrosterone, Endocrinol 97:458-468. Estrogenic and androgenic effects of long-term DHEA administration have also been observed in humans. Drucker, W. D., J. M. Blumbert, and R. David. 1966. Clin. Res. 14:279. These effects clearly limit the usefulness of DHEA as an anti-obesity agent in humans.
As a second matter, the conversion of DHEA to .alpha.-HET and .beta.-HET is sometimes accomplished intracellularly, where these products exert their biochemical effects. However, once excreted from cells to the general circulation, both .alpha.-HET and .beta.-HET are rapidly deactivated and excreted from the body. Kappas, Hillman, Fukushima, and Gallagher, The Thermogenic Effect and Metabolic Fate of Etiocholanone in Man, J. Clin. Endocrin. & Metab., 18(10), 1043. Therefore, it is apparent that gross administration of DHEA metabolites is also of limited usefulness in the treatment of obesity in humans.
The common thread to the estrogenicity and steroid de-activation problems is the presence of the hydroxyl group at the 3.beta. position of the steroid. It is known that the 3.beta.-hydroxyl group plays a major role in directing the conversion of DHEA to estrogens and androgens. Baulieu, E. E. and F. Dray, 1963, Conversion of .sup.3 H-dehydroepiandrosterone sulfate to .sup.3 H-estrogens in normal pregnant women, J. Clin. Endocrinol. Metab 23:1298; MacDonald, P. C., A. Chapdelaine, O. Gonzalez, E. Gurpide, R. L. Vande Wiele, and S. Lieberman. 1965. J. Clin. Endocrinol. Metab. 25:1557; Slaunwhite, W. R., M. J. Burgett, and A. A. Sandberg. 1967. J. Clin. Endocrinol. Metab. 27:663. It is also known that de-activation of .beta.-HET occurs by conjugation at the 3.beta. position to glucuronic acid. The present invention provides for the replacement of the hydroxyl group with a methyl group to preclude conjugation of the molecule to glucuronic acid.
Prior designs provide no information in connection with anti-obesity properties of a 3.beta.-MET derivative. U.S. Pat. No. 4,451,460 to Hansen et al. claims various methods for releasing human steroid mixtures into the air so as to repel deer, elk, moose, hare and similar animals. U.S. Pat. No. 4,657,759 to Hansen, et al. describes a matrix of thermoplastic polymer and human steroids for this use. U.S. Pat. No. 4,496,556 to Orentreich claims DHEA and its therapeutically effective derivatives for use in the treatment of dry skin. U.S. Pat. No. 4,542,129 to Orentreich describes the identical use of DHEA in conjunction with keratolytic agents to prevent the formation of acne-like skin lesions. U.S. Pat. No. 4,518,595 to Coleman, et al., describes the use of DHEA, its sulfated derivative and soluble DHEA compounds for enhancing pancreatic .beta.-cell function for the treatment of diabetes. U.S. Pat. No. 4,628,052 to Peat claims the use of DHEA and DHEA derivatives in the treatment of arthritis and joint pain. Finally, while U.S. Pat. No. 4,602,008 to Krsek describes etiocholanone derivatives useful as anti-diabetic, anti-obesity and anti-erythropoietic agents, only 16-alkylated and 16-alkylated-7-hydroxy derivatives and the esters and ethers thereof are claimed.
Therefore, an object of this invention is to provide a new method of weight reduction consisting of a steroid compound which simultaneously depresses anabolic enzymes (caloric intake) and increases metabolic rate (caloric expenditure).
It is a further object of this invention to provide a new steroid composition that duplicates the anti-obesity properties of DHEA metabolites but eliminates their inherent clinical disadvantages.
More specifically, it is another object of this invention to provide an .alpha.-methyl derivative (.alpha.-MET) of .alpha.-hydroxyetiocholanone. It is a further object of this invention to provide a .beta.-methyl derivative (.beta.-MET) of .beta.-hydroxyetiocholanone, the DHEA metabolite associated with anti-obesity activity.
It is a still further object of this invention to provide methods for administering .alpha.-MET and .beta.-MET in various pharmaceutically acceptable, therapeutically effective ways.